Calcitriol (1α,25(OH)2D3) is the hormonally active metabolite of vitamin D3. Calcitriol functions not only in the calcium homeostatic mechanisms and in support of bone mineralization but also elsewhere, inter alia, parathyroid glands, the keratinocytes, and cells of the immune system.
Primarily, calcitriol functions to elevate plasma calcium and plasma phosphorous to support bone mineralization and also to prevent neuromuscular convulsions. However, calcitriol has the effect of inducing elevated plasma calcium concentrations (hypercalcemia) when given in amounts believed to be sufficient to overcome the effects of osteoporosis.
U.S. Pat. No. 6,017,907 describes the synthesis and biological activities of a group of vitamin D analogues, including C/D cis-fused analogues. The biological activities described in this document refer to inhibition of cell proliferation, induction of cell differentiation, treatment and prevention of immune disorders, inflammatory diseases, skin disorders, hyperproliferative disorders and cancer, and improving the function of cells in which calcium is an essential regulating agent. U.S. Pat. No. 6,017,907 teaches, based on FIG. 6 showing an evaluation in rachitic chicks after treatment for ten consecutive days with three individual compounds referred as 4, 5 and 58, by measuring serum and bone calcium and serum osteocalcin, that these vitamin D analogues have strikingly lower effect on calcium and bone homoeostasis, i.e. do not have the same toxic effect as previously known vitamin D compounds. U.S. Pat. No. 6,017,907 however does not teach or suggest using these vitamin D analogues for the therapy or prevention of bone disorders such as osteoporosis, renal osteodystrophy, Paget's disease or osteomalacia.
Wu et al. in Bioorganic & Medicinal Chemistry Letters (2002) 12: 1633-1636 have disclosed the synthesis of a few seco-C-9,11-bisnor-17-methyl-1α,25-dihydroxyvitamin D3 analogues. By determining their biological activities in vitro on different cell lines, they have showed that antiproliferative activities are high, the S-epimer being the more potent within a pair of 20-epimers, and that several analogues display high ratios of differentiation between antiproliferative and calcemic effects. This document however does not teach or suggest using these vitamin D3 analogues for the therapy or prevention of bone disorders such as osteoporosis, renal osteodystrophy, Paget's disease or osteomalacia.
There is a need in the art for vitamin D3 analogues being potent bone protecting agents by selectively targeting bone formation rather than bone resorption or intestinal calcium absorption, thus leading to less calcemic effects (such as hypercalcemia or hypercalciuria) than 1,25(OH)2D3. There is also a need in the art for vitamin D3 analogues which are both efficient and safe in the treatment of bone disorders such as, but not limited to, osteoporosis, renal osteodystrophy, Paget's disease or osteomalacia.
There is a long felt need in the art for vitamin D3 compounds which have the ability to bind to the Vitamin D Receptor (VDR) and induce bone matrix formation and mineralization without the potential side effects of hypercalcemia.